The natural history and management of gastrinomas and other malignant pancreatic endocrine tumors (PET's) is largely based on antedotal reports and small series because of their relatively low incidence. Gastrinomas are the most common symptomatic, malignant PET and sufficient numbers of these patients (n=265) have been entered into our protocols to allow systematic assessment. Studies are now underway, evaluating the natural history of these tumors including the presentation and initial diagnosis, definition of factors determining prognosis and improved methods to diagnose these tumors. The diagnosis of ZES in our patients was found to be 5 years from onset. The results of an analysis in 261 patients of the clinical presentation of patients with ZES, misdiagnosis and associated conditions has now been completed and is in press in Medicine. Based on this analysis a series of important clinical parameters that should suggest the diagnosis and possibly reduce the 5-year delay in diagnosis were identified. A similar analysis is now being performed on the acid secretory parameters to identify criteria that will assist in the diagnosis of ZES. Detailed studies are also underway investigating the management of these tumors including assessment of newer methods to localize tumor extent (endoscopic ultrasound, somatostatin receptor scintigraphy [SRS]), definition of the role of surgical resection in both limited metastatic disease and patients with no hepatic metastases; the role of aggressive resection in selected patients, and the role of surgery in patients with MEN1 or without MEN1. The possible side-effects of longterm acid secretory control are being examined including effects on vitamin B-12 and iron absorption as well as the development of gastric carcinoids. Lastly, medical treatment of advanced disease by chemotherapy, use of interferon, radiation and somatostatin analogues is being examined. This last year the results of our long-term prospective study of surgery for cure in patients with ZES was reported (NEJM 341:635, 1999) involving 151 consecutive cases. This study established the value of surgery for cure in patients without MEN1, and demonstrates its ineffectiveness in patients without MEN-1.